Action Points

Point out that the study cannot determine causality and cannot distinguish whether the observations are due to toxic effects of FGF-23 or due to the fact that FGF-23 is a surrogate marker for mortality due to other factors.

Inform patients that further study and development of the FGF-23 assay may be needed before the test could be considered for clinical use.

One-year mortality risk for patients starting dialysis with the highest serum fibroblast growth factor 23 (FGF-23) levels was 5.7 times higher than for those with the lowest levels and 20% higher than for those with normal levels, reported Myles Wolf, M.D., of the University of Miami, and colleagues, in the Aug. 7 issue of the New England Journal of Medicine.

In the prospective case-control study, elevated FGF-23 levels were associated with a significantly increased mortality risk even when patients had normal levels of serum phosphate.

These results suggest FGF-23 adds to predictive ability of phosphorus levels, which "provide only a partial assessment of the risk associated with abnormal phosphorus metabolism," Dr. Wolf and colleagues said.

In an accompanying editorial, Chi-yuan Hsu, M.D., of the University of California San Francisco, wrote that the magnitude of the effect on mortality was impressive and may be the tip of the iceberg if the findings apply to the much larger population with chronic kidney disease.

The researchers agreed that FGF-23 could be an especially useful biomarker for assessing the risk of death in patients with early kidney disease, who have elevated FGF-23 levels long before elevated phosphorus develops.

"Currently, the vast majority of the estimated 20 million people with chronic kidney disease in the United States are neither advised to restrict dietary phosphorus nor treated with dietary phosphorus binders," they wrote, adding that FGF-23 measurements may identify those who need such strategies despite normal serum phosphate.

However, the test is not yet ready for routine clinical use because assays used to measure serum FGF-23 are not commercially available, Dr. Wolf said.

His group conducted a case-control analysis within the larger Accelerated Mortality on Renal Replacement (ArMORR) study. That prospective cohort study included 10,044 patients initiating dialysis at 1,056 dialysis centers across the U.S. in 2004 or 2005.

The analysis included 200 patients who died and 200 who survived during the first year of hemodialysis treatment randomly selected to represent the spectrum of phosphate levels.

As expected from prior studies, patients in the highest serum phosphate quartile with levels above 5.5 mg/dl had a significant 20% increased risk of death in the first year of dialysis compared with those who had levels of 3.5 to 4.5 mg/dl (multivariate hazard ratio 1.2, 95% confidence interval 1.1 to 1.4).

However, FGF-23 was an even stronger predictor of first-year mortality. After controlling for case-mix variables, each unit increase in log FGF-23 was associated with a 60% increase in risk of death (OR 1.6, 95% CI 1.2 to 1.9).

This association was further strengthened by adjustment for laboratory test results (OR 1.8 per unit increase, 95% CI 1.4 to 2.4) and unchanged by adjustment for 1,25-dihydroxyvitamin D level.

Each higher quartile of FGF-23 was associated with greater mortality risk in the multivariate analysis. Compared with patients in the lowest quartile with FGF-23 levels less than 1,090 reference units/ml, the odds ratios were:

1.6 for those with levels of 1,090 to 1,750 RU/ml (95% CI 0.8 to 3.3).

4.5 for those with levels of 1,751 to 4,010 RU/ml (95% CI 2.2 to 9.4).

5.7 for those in the highest quartile with levels above 4,010 RU/ml (95% CI 2.6 to 12.6).

The significant risks for both groups with above-average levels were unchanged after further adjustment for subsequent therapy with activated vitamin D and for prior therapy with phosphorus binders and exclusion of patients treated with binders.

FGF-23 levels were 22% lower in blacks and 34% lower in Hispanics than in whites. Racial, but not ethnic, differences extended to mortality risk with the odds of death 60% lower for blacks than whites given the same low FGF-23 levels (OR 0.4, 95% CI 0.2 to 0.7).

"The question of whether decreased FGF-23 levels might contribute to the well-known but poorly understood survival advantage of blacks who are undergoing dialysis is also intriguing," Dr. Wolf's group said.

The study was limited by the lack of data on dietary phosphorus intake and outcomes past one year, the researchers said. The study also could not determine whether elevated FGF-23 levels were directly toxic or a surrogate marker, they said.

The study was supported by the American Kidney Fund Clinical Scientist in Nephrology Fellowship and by grants from the American Society of Nephrology-Alaska Kidney Foundation, the Center for D-Receptor Activation Research at the Massachusetts General Hospital, and the National Institutes of Health.

Dr. Wolf reported having a pending patent application on FGF-23 measurements as a diagnostic aid and receiving consulting and lecture fees from Abbott, Genzyme, and INEOS and grant support from Shire. One co-author reported holding an active patent on the C-terminal FGF-23 assay manufactured by Immutopics; another reported receiving consulting and lecture fees from Abbott and Genzyme and grant support from Abbott.

Dr. Hsu reported no conflicts of interest.

Reviewed by Zalman S. Agus, MD Emeritus Professor University of Pennsylvania School of Medicine

Accessibility Statement

At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.